The purpose of this renewal application is to continue our Offspring-of-Twins (OOT) study of the development and course of substance use disorder (SUD) in 839 offspring who are at different levels of environmental and genetic risks by virtue of the SUD status of their twin-father and that of his co-twin. Our OOT design is unique in distinguishing 4 groups of offspring: (1) Offspring whose fathers have a history of illicit drug dependence, with or without a history of alcohol dependence (SUD) are at both High Genetic and High Environmental risk ("HG-HE");(2) Offspring of unaffected fathers whose cotwin has a history of SUD are at High Genetic but Low Environmental risk (by virtue of a rearing environment without an affected father - "HG-LE");(3) Offspring of unaffected fathers whose DZ cotwin has SUD/AD are at Moderate Genetic risk and Low Environmental risk ("MG-LE");(4) Offspring of unaffected men (no SUD) with unaffected cotwins are at Low Genetic and Low Environmental risk ("LG-LE"). During the first funding period, comprehensive psychiatric diagnostic interviews were administered to parents (at T1 only) and to offspring (at T1 and T2, approximately 2 years apart). We have been successful in recruiting and assessing the needed sample during our first grant period, and emergent findings provide the foundation on which this renewal application is based. Analyses of baseline data indicate a strong effect of high genetic risk. HG offspring are significantly more likely to have DSM-IV cannabis abuse/dependence regardless of level of environmental risk as compared to MG and LG risk offspring. Analyses of baseline data also indicate that specific environmental variables contribute to offspring SUD after adjusting for genetic factors. Close parent- offspring and sibling relationships are protective, while offspring are at increased risk for SUD if their siblings and peers use drugs, alcohol and smoke. Psychological trauma and co-morbid psychopathology have also been investigated as mediators of the genetic and family environmental influences. During our next grant period, we propose a 3rd (T3) and 4th (T4) assessment of the offspring (on average age 22 at T1) as they age into their mid to late twenties. This period of life, known as "emerging adulthood," is a peak period for transitions in substance use involvement, remission and persistence. It is essential that these additional assessments be conducted so that the developmental course of SUD can be characterized and key hypotheses related to mediation and moderation of young adult outcomes tested. In addition, our sister project, the Children of Alcoholic Twins (COAT) is currently in the field for a 3rd and 4th follow-up. This application will permit continued complementary analyses of the COAT and TAP data to elucidate the complex interplay of genetic, rearing environment and specified adult psychosocial domains in the etiology of SUD.